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The conundrum of CD40 function: host protection or disease promotion?
Opinion
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Vol.22 No.3 March 2006
The conundrum of CD40 function: host protection or disease promotion? Ram K. Mathur, Amit Awasthi and Bhaskar Saha National Centre for Cell Science, Ganeshkhind, Pune 411 007, India
T cells regulate the immune responses to pathogens and autoantigens. The immune responses are tolerizing or anti-inflammatory against autoantigens but are inflammatory against pathogens and allografts. Such contradictory immune responses have been attributed to two counteracting effector cell types or to two counterregulatory sets of molecules: cell-surface expressed or secreted. By contrast, recent reports suggest that CD40, a co-stimulatory molecule on antigen-presenting cells, is a crucial controller of these counteractive immune responses, and emphasize reciprocal inhibition as an essential feature of biological responses. The molecular mechanism of such reciprocity in CD40 functions is the basis of immunotherapy in many diseases. Immune regulation The mechanism of immune activation has a crucial role in determining the outcome of an infection; an appropriate activation of cell-mediated immunity eliminates intracellular infections, and a finely tuned humoral immune response mediates antibody-dependent elimination of extracellular infections [1]. Whereas an inadequate response or a suppressive response to either of these types of infection results in persistence of the pathogen, an exaggerated response eliminates the pathogen but results in hypersensitivity reactions. In both cases, the host suffers from the destruction of its own tissues. However, the same suppressive response is the key to maintaining self-tolerance, avoiding autoimmune responses and allografts. Thus, this modus operandi of the immune system implies that an immune response is balanced by counterregulatory or reciprocal principles (Figure 1). In this article, using a model of CD40–CD40 ligand (CD40L) interaction, we justify that a reciprocal principle of immune regulation such as this does not need to be regulated by counteracting cells or molecules but can also be achieved by a single receptor–ligand pair, which expressly seems to be a paradox but eventually turns out to be a fine-tuner that maintains immune homeostasis. Reciprocal inhibition as a principle of biological response regulation As the metazoans evolved, the biological control systems also developed and became increasingly sophisticated. Among these control systems, the principle of reciprocal regulation remains a key control mechanism that Corresponding author: Saha, B. ([email protected]). Available online 30 January 2006
regulates a wide range of physiological processes, from the reciprocal regulation of blood sugar level by insulin and glucagon to the counterregulation of cardiorespiratory and many other physiological functions by the sympathetic and parasympathetic nervous systems. Similarly, in the immune system, the regulatory cells, the responders and the cell-surface expressed or secreted molecules that take part in this regulation seem to follow this principle of reciprocity while in action. For example, the delayed-type hypersensitivity response (DTH) is mediated primarily by T helper (Th)1 cells, alternatively proposed as DTHmediating T cells (TDTH) that secrete interleukin (IL)-2 and interferon (IFN)-g, but has been shown to be suppressed by counterregulatory Th2 cells that secrete IL-4, IL-5 and IL-10 [2,3]. Preincubation of macrophages with IL-4 downregulates the IFN-g-induced activation of macrophages and the elimination of the amastigotes of the protozoan parasite Leishmania [4]. In this case, two different cells, Th1 and Th2, are reciprocally modulating the same immune response, such as DTH or the killing of Leishmania. Likewise, although both CD28 and cytotoxic T-lymphocyte-associated antigen-4 belong to the Ig superfamily and are expressed on the same T cell, T-cell receptor (TCR)-triggered T-cell proliferation and IL-2 secretion were potentiated by CD28 but reduced by cytotoxic T-lymphocyte-associated antigen-4 [5,6]. Similarly, IFN-g and IL-4 counterregulate both the switching of IgM to IgG1 and IgG2a, respectively, and the IgE-induced secretion of mast cell granules [7,8]. By contrast, CD40, a co-stimulatory molecule expressed on macrophages, dendritic cells and B cells [9], seems to present a conundrum in this principle of reciprocity because this single molecule can signal through two different pathways reciprocally to result in counteractive immune responses. CD40 function: immune activation versus immunosuppression Antigen-presenting cells (APCs) provide two signals to T cells to regulate the activation or suppression of antigenspecific T cells: (i) MHC–antigen–TCR ternary complexes and (ii) co-stimulatory molecules [5,6,10]. The co-stimulatory molecules of the B7 family, such as B7.1 and B7.2, and of the tumor necrosis factor (TNF) receptor family, such as CD40, have pivotal roles in T-cell co-stimulation and activation [11]. CD40 interacts with CD40L on activated T cells and helps in immune activation during bacterial, fungal, parasitic and viral infections [12]. Previously, the CD40–CD40L interaction was proposed
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Figure 1. CD40-induced reciprocal regulation of the inflammatory (IL-12 and TNF-a) and anti-inflammatory (TGF-b and IL-10) cytokines. BALB/c-derived macrophages were stimulated with the indicated doses of anti-CD40 antibody. RNA was extracted eight hours after stimulation, and reverse-transcription–PCR was performed. The densitometric data of the CD40-induced cytokine production were plotted as a graph. Some of the representative data have been published previously [48]. The data suggest that the expression levels of CD40 on APCs might result in counteracting immune responses.
to signal to the T cells that co-stimulate the TCR-triggered T cells [13]. Thus, the earlier views maintained that the CD40–CD40L interaction potentiated the TCR-mediated activation of T cells, which then secreted cytokines to activate the interacting APCs. Indeed, the antileishmanial function of CD40 was proposed to be T-cell-centric [14] and was never viewed independently of T-cell effector functions. However, recent observations suggest that this interaction can activate the CD40-expressing APCs such as macrophages and dendritic cells via CD40 signaling [9] (Figure 2). The CD40 signal induces the production of TNF-a and IL-12: a proinflammatory and a Th1-differentiating cytokine, respectively [15]. Th1 cells are proposed to be instrumental in host protection against intracellular parasitic infections (e.g. Leishmania) [16]. Thus, CD40 not only has a central role in immune activation during infection and inflammatory responses, but might also induce the inflammatory reactions that cause tissue damage. Thus, anti-inflammatory cytokines such as IL-4, IL-10, IL-13 and transforming growth factor (TGF) b, which are known to restrict IFN-g-mediated tissue damage [17–20], are required for maintaining immune homeostasis. CD40 induces IL-10 and TGF-b in macrophages (Figure 1), thereby limiting the Th1 response. These findings suggest that CD40 executes
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Figure 2. The interaction between CD40 and CD40L in immune regulation. T-cell-expressed CD40L interacts with CD40 on APCs and induces different effector functions. The CD40–CD40L interaction not only helps T-cell co-stimulation and differentiation of effector T cells (e.g. Th1, Th2 and Treg) but also activates macrophages, dendritic cells (DCs) and B cells. (a) In B cells, the interaction between CD40 and CD40L rescues the cells from Ig-induced apoptosis and helps antibody production, class switching and affinity maturation. (b) The CD40–CD40L interaction activates macrophages to secrete proinflammatory mediators such as TNF-a and IL-12 (required for setting a Th1 bias), to induce free radical and nitric oxide production (required for antimicrobial functions) and to enhance the antigen-presenting capacity (required for T-cell activation). (c) The CD40–CD40L interaction induces the maturation of DCs and, consequently, regulates antigen-presenting functions and immune activation. www.sciencedirect.com
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two contrasting effector functions, immune activation and immunosuppression, resulting in the conundrum of CD40 function: How does a single molecule regulate counteractive effector functions? We propose that the differential role of CD40 in immune activation and immunosuppression depends on the strength of CD40 signaling. At higher doses of anti-CD40 antibody-mediated crosslinking, CD40 induces the production of IL-12 and TNF-a, whereas at lower doses of crosslinking, CD40 induces production of IL-10 and TGF-b from macrophages (Figure 1).
production [30], CD40 stimulation ameliorates the infection [31]. The host-protective effect of CD40 is also observed in a vaccination model, in which CD40 stimulation was shown to enhance the vaccination with weak antigens of Listeria [32]. Likewise, CD40-induced macrophage activation helps to induce protective immunity against Salmonella dublin [33]. Similar observations were recorded in Cryptococcus [34], Pneumocystis carinii [35] and Candida albicans [36] infections. CD40 is also shown to have important roles in intracellular parasite infections such as Trypanosoma cruzi [37] and Leishmania. Both CD40K/K and CD40LK/K mice were more susceptible to Leishmania infection than were their wild-type littermates [14,38,39], and the increased susceptibility was associated with diminished IL-12, IFN-g and inducible nitric oxide synthetase (iNOS) 2 induction in macrophages. Similarly, in vivo administration of an agonistic anti-CD40 antibody resulted in lower levels of parasitic infection than were observed in the control mice [40]. Although the antileishmanial function of CD40 was proposed to be associated with the Th1 immune response, the report did not preclude the possibility of an IFN-g-independent antileishmanial function of CD40 [40,41]. In addition to being required in combating intracellular parasitic infections, CD40 was shown to maintain host-protective immunity to extracellular parasite, which was associated with a Th2 response [42]. These observations suggested that the
The CD40–CD40L interaction and immune activation CD40L has been proposed to signal and co-stimulate CD4CT-cell proliferation, resulting in IL-4, IFN-g and IL-10 production [21–24]. By contrast, CD40 crosslinking by a monoclonal anti-CD40 antibody induces proliferation and tyrosine phosphorylation in B cells, suggesting that CD40 is a receptor that signals [25]. Indeed, CD40 signals through nuclear factor-kB to induce IL-12 production from APCs [26], and IL-12 selectively enhances CD40Lmediated IFN-g production [27]. In addition, soluble CD40L was shown to induce IL-10 production [28], and IL-10 overexpression in APCs resulted in exaggerated susceptibility to Leishmania infection [29]. These observations led to the concept that the CD40–CD40L interaction activates APCs via CD40 signals, thereby modulating the course of many infectious diseases. Whereas CD40 deficiency aggravates Mycobacterium avium infection associated with less IL-12 and IFN-g CD40–CD40LHi
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Figure 3. Proposed reciprocal regulation of T-cell functions and macrophage activation as a function of the extent of CD40–CD40L crosslinking. High levels of CD40–CD40L interaction activate macrophages and induce the production of IL-12, which skews Th0 (the precursor of Th subsets) to Th1. By contrast, low levels of interaction between CD40 and CD40L induce the production of IL-10, TGF-b and IL-2low from T cells, resulting in the deactivation of macrophages and the generation of Th2 and Treg cells. www.sciencedirect.com
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interaction between CD40 and CD40L could induce both Th1 and Th2 immune responses. As in all other infections, Th1-type and Th2-type responses were also implicated in HIV infection [43]. The induction of the Th1 differentiation-inducing cytokine IL-12 is shown to be defective owing to downregulation of CD40L on CD4CT cells in HIV patients [44]. Because the CD4CT-cell-expressed CD40L interacts with CD40 on CD8CT cells, enhancing the generation of memory CD8CT cells [45], CD40 signaling in CD8CT cells remains to be correlated with their effector functions, such as controlling viral replication and HIV-suppressive b-chemokine induction [46]. CD40 is also required for the production of anti-HIV antibodies [47]. Altogether, these studies indicate that CD40 does activate the immune system to protect the host. CD40-induced immunosuppression Because the host and the pathogens (parasites in particular) coevolved, pathogens might devise strategies to bypass or subvert the CD40-induced host-protective immune responses at two levels: first, downregulation of CD40 functions and, second, induction of T cells with suppressor functions. Because CD40 has been shown to induce IL-10 in macrophages [48] and TGF-b production in B cells [49], the TGF-b production from Leishmania-infected macrophages [50] might be induced by CD40. Because these cytokines might execute immunosuppression, favoring the persistence of pathogens such as Leishmania [48,50], an indiscriminate suppression of CD40 functions would prove detrimental to these pathogens. Therefore, it is logical to assume that pathogens might differentially regulate the CD40-induced production of both antiparasitic and pro-parasitic cytokines. Indeed, in Leishmania-infected macrophages, CD40-induced IL-10 secretion is increased, whereas IL-12 production is reduced [48], setting up the paradox of CD40 functions that favor both the parasite and the host. By contrast, the regulatory T cells (Tregs) with suppressor functions were proposed to maintain immune homeostasis. Both CD40-deficient mice and antiCD40L antibody-treated mice have fewer Treg cells in peripheral blood, thymus and spleen, suggesting that CD40 has a key role in Treg generation [51]. CD40deficient mice failed to maintain injected wild-type Treg cells, suggesting a role for CD40 in creating the milieu required for Treg maintenance. Because CD40 can induce the countereffective cytokines IL-12 and TNF-a versus IL-10 and TGF-b, as a function of strength of CD40 signaling, it is possible that Treg cells maintain low CD40L expression levels on their surface, or that the APCs responsible for Treg generation express low level of CD40. Thus, the nature of the CD40 signal might control the generation and maintenance of Treg cells (Figure 3). CD40 at the molecular level: reciprocal regulation of mitogen-activated protein kinases The preceding discussion indicates that CD40 stimulation can lead to either stimulatory or suppressive immune reactions. However, the molecular mechanisms remain unknown. We have shown that CD40 crosslinking at high doses results in p38 mitogen-activated protein (MAP) www.sciencedirect.com
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kinase-dependent IL-12 induction, whereas it induces extracellular-signal-regulated kinase (ERK)-1 and ERK2-mediated IL-10 production at low doses [48]. p38MAP kinase and ERK are known to be reciprocally regulated because inhibition of one activates the other and vice versa. During Leishmania infection, the levels of CD40induced ERK-1 and ERK-2 phosphorylation and IL-10 production increase, whereas the reverse profile was observed with p38MAPK activation and IL-12 production. These observations not only explain the paradox of CD40 functions eliciting both inflammatory and antiinflammatory immune responses, but also exemplify how pathogens manipulate the CD40 signal to render a hostile cell as their ‘safe home’ (Figure 4). Future perspectives The observed conundrum of CD40 functions not only reveals a new facet of immune homeostasis, but also helps to formulate immune intervention strategies. On the one hand, this phenomenon shows how CD40 can maintain the host-protective immunity in a reciprocal setup. During infection, CD40-activated T-cell responses eliminate pathogens, whereas in healthy individuals, they maintain immune silence by regulating Treg populations. Therefore, it is possible to devise a strategy for silencing immune reactivity against the allograft or against autoantigens. On the other hand, it remains to be explored how the
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Figure 4. Proposed molecular mechanism of the reciprocal regulation of CD40induced counteractive effector functions. At high doses of crosslinking, CD40 activates p38MAP kinase to induce IL-12 and iNOS2. Whereas IL-12 induces Th1 cells, iNOS2 catalyzes the generation of nitric oxide, the free radical that kills Leishmania amastigotes. At lower doses of crosslinking, CD40 activates ERK-1 and ERK-2, thereby inducing IL-10, which works in an autocrine manner to inhibit the CD40-induced activation of p38MAP kinase and the induction of IL-12 and iNOS2, resulting in disease promotion. IL-10 also has a role in Treg generation and maintenance. Thus, CD40 can provide both host protection and disease promotion by triggering reciprocal signaling pathways as a function of the extent of crosslinking. The other possible factors in this reciprocity of CD40 signaling could involve the differential recruitment of TNF-a-receptor-associated factors (TRAFs) 1–6 and phosphatases.
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initial CD40 ligation results in differential activation of p38MAP kinase or ERK-1 and ERK-2. The bifurcation of CD40 signaling might occur upstream of these MAP kinases (Figure 4) or right on the membrane, owing to differential clustering of CD40 with different signaling molecules. The importance of receptor clustering has been implicated not only in CD40 signaling [52], but also in TNF receptor signaling [53–56]. In addition, despite a great beneficial effect of anti-CD40 antibody administration in the mouse [48], recent reports on the role of Toll-like receptors in various immune responses suggest that, in vivo, a source of Toll-like receptor stimulation is necessary for an optimal effect of CD40 signal manipulation [57,58]. Nevertheless, more in vivo work is required to validate fully all of this interesting information derived from in vitro experimentation. Acknowledgements Our work is supported by the Department of Biotechnology, Government of India. R.K.M. and A.A. are supported by a fellowship from the Indian Council of Medical Research and the Council of Scientific and Industrial Research, respectively. We thank Debashis Mitra for critically reviewing the manuscript. Many references could not be cited owing to space constraints.
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16 Scott, P. (1991) IFN-gamma modulates the early development of Th1 and Th2 responses in a murine model of cutaneous leishmaniasis. J. Immunol. 147, 3149–3155 17 Wurtz, O. et al. (2004) IL-4-mediated inhibition of IFN-gamma production by CD4CT cells proceeds by several developmentally regulated mechanisms. Int. Immunol. 16, 501–508 18 Akdis, C.A. and Blaser, K. (2001) Mechanisms of interleukin-10mediated immune suppression. Immunology 103, 131–136 19 Wynn, T.A. (2003) IL-13 effector functions. Annu. Rev. Immunol. 21, 425–456 20 Gorelik, L. et al. (2002) Mechanism of transforming growth factor beta-induced inhibition of T helper type 1 differentiation. J. Exp. Med. 195, 1499–1505 21 Peng, X. et al. (1996) Accessory signaling by CD40 for T cell activation: induction of Th1 and Th2 cytokines and synergy with interleukin-12 for interferon-gamma production. Eur. J. Immunol. 26, 1621–1627 22 Blotta, M.H. et al. (1996) Cross-linking of the CD40 ligand on human CD4CT lymphocytes generates a costimulatory signal that upregulates IL-4 synthesis. J. Immunol. 156, 3133–3140 23 Cayabyab, M. et al. (1994) CD40 preferentially costimulates activation of CD4CT lymphocytes. J. Immunol. 152, 1523–1531 24 Armitage, R.J. et al. (1993) CD40 ligand is a T cell growth factor. Eur. J. Immunol. 23, 2326–2331 25 Valle, A. et al. (1989) Activation of human B lymphocytes through CD40 and interleukin 4. Eur. J. Immunol. 19, 1463–1467 26 Yoshimoto, T. et al. (1997) Induction of interleukin-12 p40 transcript by CD40 ligation via activation of nuclear factor-kappa B. Eur. J. Immunol. 27, 3461–3470 27 Mendez-Samperio, P. et al. (1999) Interleukin-12 regulates the production of Bacille Calmette-Guerin-induced interferon-gamma from human cells in a CD40-dependent manner. Scand. J. Immunol. 50, 61–67 28 Foey, A.D. et al. (2001) CD40 ligation induces macrophage IL-10 and TNF-alpha production: differential use of the PI3K and p42/44 MAPKpathways. Cytokine 16, 131–142 29 Groux, H. et al. (1999) A transgenic model to analyze the immunoregulatory role of IL-10 secreted by antigen-presenting cells. J. Immunol. 162, 1723–1729 30 Florido, M. et al. (2004) CD40 is required for the optimal induction of protective immunity to Mycobacterium avium. Immunology 111, 323–327 31 Lazarevic, V. et al. (2003) CD40, but not CD40L, is required for the optimal priming of T cells and control of aerosol M. tuberculosis infection. Immunity 19, 823–835 32 Rolph, M.S. and Kaufmann, S.H. (2001) CD40 signaling converts a minimally immunogenic antigen into a potent vaccine against the intracellular pathogen Listeria monocytogenes. J. Immunol. 166, 5115–5121 33 Marriott, I. et al. (1999) CD40–CD40 ligand interactions augment survival of normal mice, but not CD40 ligand knockout mice, challenged orally with Salmonella dublin. Infect. Immun. 67, 5253–5257 34 Pietrella, D. et al. (2004) Disruption of CD40/CD40L interaction influences the course of Cryptococcus neoformans infection. FEMS Immunol. Med. Microbiol. 40, 63–70 35 Wiley, J.A. and Harmsen, A.G. (1995) CD40 ligand is required for resolution of Pneumocystis carinii pneumonia in mice. J. Immunol. 155, 3525–3529 36 Netea, M.G. et al. (2002) CD40/CD40 ligand interactions in the host defense against disseminated Candida albicans infection: the role of macrophage-derived nitric oxide. Eur. J. Immunol. 32, 1455–1463 37 Chaussabel, D. et al. (1999) CD40 ligation prevents Trypanosoma cruzi infection through interleukin-12 upregulation. Infect. Immun. 67, 1929–1934 38 Campbell, K.A. et al. (1996) CD40 ligand is required for protective cellmediated immunity to Leishmania major. Immunity 4, 283–289 39 Soong, L. et al. (1996) Disruption of CD40–CD40 ligand interactions results in an enhanced susceptibility to Leishmania amazonensis infection. Immunity 4, 263–273 40 Awasthi, A. et al. (2003) CD40 signaling is impaired in L. majorinfected macrophages and is rescued by a p38MAPK activator establishing a host-protective memory T cell response. J. Exp. Med. 197, 1037–1043
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41 Andrade, R.M. et al. (2003) CD154 activates macrophage antimicrobial activity in the absence of IFN-gamma through a TNF-alphadependent mechanism. J. Immunol. 171, 6750–6756 42 Khan, W.I. et al. (2005) Disruption of CD40–CD40 ligand pathway inhibits the development of intestinal muscle hypercontractility and protective immunity in nematode infection. Am. J. Physiol. Gastrointest. Liver Physiol. 288, G15–G22 43 Maggi, E. et al. (1994) Ability of HIV to promote a TH1 to TH0 shift and to replicate preferentially in TH2 and TH0 cells. Science 265, 244–248 44 Vanham, G. et al. (1999) Decreased CD40 ligand induction in CD4 T cells and dysregulated IL-12 production during HIV infection. Clin. Exp. Immunol. 117, 335–342 45 Bourgeois, C. et al. (2002) A role for CD40 expression on CD8CT cells in the generation of CD8CT cell memory. Science 297, 2060–2063 46 Cotter, R.L. et al. (2001) Regulation of human immunodeficiency virus type 1 infection, beta-chemokine production, and CCR5 expression in CD40L-stimulated macrophages: immune control of viral entry. J. Virol. 75, 4308–4320 47 Conge, A.M. et al. (1998) Impairment of B-lymphocyte differentiation induced by dual triggering of the B-cell antigen receptor and CD40 in advanced HIV-1-disease. AIDS 12, 1437–1449 48 Mathur, R.K. et al. (2004) Reciprocal CD40 signals through p38MAPK and ERK-1/2 induce counteracting immune responses. Nat. Med. 10, 540–544 49 Zan, H. et al. (1998) CD40 engagement triggers switching to IgA1 and IgA2 in human B cells through induction of endogenous TGF-beta:
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evidence for TGF-beta but not IL-10-dependent direct S mu/S alpha and sequential S mu/S gamma. S gamma/S alpha DNA recombination. J. Immunol. 161, 5217–5225 Gantt, K.R. et al. (2003) Activation of TGF-beta by Leishmania chagasi: importance for parasite survival in macrophages. J. Immunol. 170, 2613–2620 Guiducci, C. et al. (2005) CD40/CD40L interaction regulates CD4CCD25CT-reg homeostasis through dendritic cell-produced IL2. Eur. J. Immunol. 35, 557–567 Vidalain, P.O. et al. (2000) CD40 signaling in human dendritic cells is initiated within membrane rafts. EMBO J. 19, 3304–3313 Grassme, H. et al. (2002) Clustering of CD40 ligand is required to form a functional contact with CD40. J. Biol. Chem. 277, 30289-30299. Erratum in 277, 36904 Morris, A.E. et al. (1999) Incorporation of an isoleucine zipper motif enhances the biological activity of soluble CD40L (CD154). J. Biol. Chem. 274, 418–423 Chen, G. and Goeddel, D.V. (2002) TNF-R1 signaling: a beautiful pathway. Science 296, 1634–1635 Liu, Z.G. et al. (1996) Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-kappaB activation prevents cell death. Cell 87, 565–576 Schulz, O. et al. (2000) CD40 triggering of heterodimeric IL-12 p70 production by dendritic cells in vivo requires a microbial priming signal. Immunity 13, 453–462 Krug, A. et al. (2001) Toll-like receptor expression reveals CpG DNA as a unique microbial stimulus for plasmacytoid dendritic cells which synergizes with CD40 ligand to induce high amounts of IL-12. Eur. J. Immunol. 31, 3026–3037
ICOPA XI International Congress of Parasitology 6–11 August 2006, Scottish Exhibition and Conference Centre Glasgow, UK The scientific programme covers a diversity of research areas and is directed at a global audience. Although there are many defined themes, there is scope for presentations about any aspect of parasitology. The full programme also contains over 200 invited speakers, covering a broad range of expertise. This is the world’s largest parasitology congress, and Glasgow provides an excellent venue in which to hold it. We hope that you will attend and also encourage your colleagues to do so. We look forward to seeing you there. Register early at a reduced rate until 17 March 2006. (You are invited to contact the secretariat to discuss the possibility of late abstract submission.) For further information and online registration, go to www.icopaxi.org ICOPA XI Conference Secretariat c/o Meeting Makers Jordanhill Campus 76 Southbrae Drive Glasgow UK G13 1PP Tel: +44 (0) 141 434 1500 Fax: +44 (0)141 434 1500 Email: [email protected]
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The conundrum of CD40 function: host protection or disease promotion? Ram K. Mathur, Amit Awasthi and Bhaskar Saha National Centre for Cell Science, Ganeshkhind, Pune 411 007, India
T cells regulate the immune responses to pathogens and autoantigens. The immune responses are tolerizing or anti-inflammatory against autoantigens but are inflammatory against pathogens and allografts. Such contradictory immune responses have been attributed to two counteracting effector cell types or to two counterregulatory sets of molecules: cell-surface expressed or secreted. By contrast, recent reports suggest that CD40, a co-stimulatory molecule on antigen-presenting cells, is a crucial controller of these counteractive immune responses, and emphasize reciprocal inhibition as an essential feature of biological responses. The molecular mechanism of such reciprocity in CD40 functions is the basis of immunotherapy in many diseases. Immune regulation The mechanism of immune activation has a crucial role in determining the outcome of an infection; an appropriate activation of cell-mediated immunity eliminates intracellular infections, and a finely tuned humoral immune response mediates antibody-dependent elimination of extracellular infections [1]. Whereas an inadequate response or a suppressive response to either of these types of infection results in persistence of the pathogen, an exaggerated response eliminates the pathogen but results in hypersensitivity reactions. In both cases, the host suffers from the destruction of its own tissues. However, the same suppressive response is the key to maintaining self-tolerance, avoiding autoimmune responses and allografts. Thus, this modus operandi of the immune system implies that an immune response is balanced by counterregulatory or reciprocal principles (Figure 1). In this article, using a model of CD40–CD40 ligand (CD40L) interaction, we justify that a reciprocal principle of immune regulation such as this does not need to be regulated by counteracting cells or molecules but can also be achieved by a single receptor–ligand pair, which expressly seems to be a paradox but eventually turns out to be a fine-tuner that maintains immune homeostasis. Reciprocal inhibition as a principle of biological response regulation As the metazoans evolved, the biological control systems also developed and became increasingly sophisticated. Among these control systems, the principle of reciprocal regulation remains a key control mechanism that Corresponding author: Saha, B. ([email protected]). Available online 30 January 2006
regulates a wide range of physiological processes, from the reciprocal regulation of blood sugar level by insulin and glucagon to the counterregulation of cardiorespiratory and many other physiological functions by the sympathetic and parasympathetic nervous systems. Similarly, in the immune system, the regulatory cells, the responders and the cell-surface expressed or secreted molecules that take part in this regulation seem to follow this principle of reciprocity while in action. For example, the delayed-type hypersensitivity response (DTH) is mediated primarily by T helper (Th)1 cells, alternatively proposed as DTHmediating T cells (TDTH) that secrete interleukin (IL)-2 and interferon (IFN)-g, but has been shown to be suppressed by counterregulatory Th2 cells that secrete IL-4, IL-5 and IL-10 [2,3]. Preincubation of macrophages with IL-4 downregulates the IFN-g-induced activation of macrophages and the elimination of the amastigotes of the protozoan parasite Leishmania [4]. In this case, two different cells, Th1 and Th2, are reciprocally modulating the same immune response, such as DTH or the killing of Leishmania. Likewise, although both CD28 and cytotoxic T-lymphocyte-associated antigen-4 belong to the Ig superfamily and are expressed on the same T cell, T-cell receptor (TCR)-triggered T-cell proliferation and IL-2 secretion were potentiated by CD28 but reduced by cytotoxic T-lymphocyte-associated antigen-4 [5,6]. Similarly, IFN-g and IL-4 counterregulate both the switching of IgM to IgG1 and IgG2a, respectively, and the IgE-induced secretion of mast cell granules [7,8]. By contrast, CD40, a co-stimulatory molecule expressed on macrophages, dendritic cells and B cells [9], seems to present a conundrum in this principle of reciprocity because this single molecule can signal through two different pathways reciprocally to result in counteractive immune responses. CD40 function: immune activation versus immunosuppression Antigen-presenting cells (APCs) provide two signals to T cells to regulate the activation or suppression of antigenspecific T cells: (i) MHC–antigen–TCR ternary complexes and (ii) co-stimulatory molecules [5,6,10]. The co-stimulatory molecules of the B7 family, such as B7.1 and B7.2, and of the tumor necrosis factor (TNF) receptor family, such as CD40, have pivotal roles in T-cell co-stimulation and activation [11]. CD40 interacts with CD40L on activated T cells and helps in immune activation during bacterial, fungal, parasitic and viral infections [12]. Previously, the CD40–CD40L interaction was proposed
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Figure 1. CD40-induced reciprocal regulation of the inflammatory (IL-12 and TNF-a) and anti-inflammatory (TGF-b and IL-10) cytokines. BALB/c-derived macrophages were stimulated with the indicated doses of anti-CD40 antibody. RNA was extracted eight hours after stimulation, and reverse-transcription–PCR was performed. The densitometric data of the CD40-induced cytokine production were plotted as a graph. Some of the representative data have been published previously [48]. The data suggest that the expression levels of CD40 on APCs might result in counteracting immune responses.
to signal to the T cells that co-stimulate the TCR-triggered T cells [13]. Thus, the earlier views maintained that the CD40–CD40L interaction potentiated the TCR-mediated activation of T cells, which then secreted cytokines to activate the interacting APCs. Indeed, the antileishmanial function of CD40 was proposed to be T-cell-centric [14] and was never viewed independently of T-cell effector functions. However, recent observations suggest that this interaction can activate the CD40-expressing APCs such as macrophages and dendritic cells via CD40 signaling [9] (Figure 2). The CD40 signal induces the production of TNF-a and IL-12: a proinflammatory and a Th1-differentiating cytokine, respectively [15]. Th1 cells are proposed to be instrumental in host protection against intracellular parasitic infections (e.g. Leishmania) [16]. Thus, CD40 not only has a central role in immune activation during infection and inflammatory responses, but might also induce the inflammatory reactions that cause tissue damage. Thus, anti-inflammatory cytokines such as IL-4, IL-10, IL-13 and transforming growth factor (TGF) b, which are known to restrict IFN-g-mediated tissue damage [17–20], are required for maintaining immune homeostasis. CD40 induces IL-10 and TGF-b in macrophages (Figure 1), thereby limiting the Th1 response. These findings suggest that CD40 executes
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Figure 2. The interaction between CD40 and CD40L in immune regulation. T-cell-expressed CD40L interacts with CD40 on APCs and induces different effector functions. The CD40–CD40L interaction not only helps T-cell co-stimulation and differentiation of effector T cells (e.g. Th1, Th2 and Treg) but also activates macrophages, dendritic cells (DCs) and B cells. (a) In B cells, the interaction between CD40 and CD40L rescues the cells from Ig-induced apoptosis and helps antibody production, class switching and affinity maturation. (b) The CD40–CD40L interaction activates macrophages to secrete proinflammatory mediators such as TNF-a and IL-12 (required for setting a Th1 bias), to induce free radical and nitric oxide production (required for antimicrobial functions) and to enhance the antigen-presenting capacity (required for T-cell activation). (c) The CD40–CD40L interaction induces the maturation of DCs and, consequently, regulates antigen-presenting functions and immune activation. www.sciencedirect.com
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two contrasting effector functions, immune activation and immunosuppression, resulting in the conundrum of CD40 function: How does a single molecule regulate counteractive effector functions? We propose that the differential role of CD40 in immune activation and immunosuppression depends on the strength of CD40 signaling. At higher doses of anti-CD40 antibody-mediated crosslinking, CD40 induces the production of IL-12 and TNF-a, whereas at lower doses of crosslinking, CD40 induces production of IL-10 and TGF-b from macrophages (Figure 1).
production [30], CD40 stimulation ameliorates the infection [31]. The host-protective effect of CD40 is also observed in a vaccination model, in which CD40 stimulation was shown to enhance the vaccination with weak antigens of Listeria [32]. Likewise, CD40-induced macrophage activation helps to induce protective immunity against Salmonella dublin [33]. Similar observations were recorded in Cryptococcus [34], Pneumocystis carinii [35] and Candida albicans [36] infections. CD40 is also shown to have important roles in intracellular parasite infections such as Trypanosoma cruzi [37] and Leishmania. Both CD40K/K and CD40LK/K mice were more susceptible to Leishmania infection than were their wild-type littermates [14,38,39], and the increased susceptibility was associated with diminished IL-12, IFN-g and inducible nitric oxide synthetase (iNOS) 2 induction in macrophages. Similarly, in vivo administration of an agonistic anti-CD40 antibody resulted in lower levels of parasitic infection than were observed in the control mice [40]. Although the antileishmanial function of CD40 was proposed to be associated with the Th1 immune response, the report did not preclude the possibility of an IFN-g-independent antileishmanial function of CD40 [40,41]. In addition to being required in combating intracellular parasitic infections, CD40 was shown to maintain host-protective immunity to extracellular parasite, which was associated with a Th2 response [42]. These observations suggested that the
The CD40–CD40L interaction and immune activation CD40L has been proposed to signal and co-stimulate CD4CT-cell proliferation, resulting in IL-4, IFN-g and IL-10 production [21–24]. By contrast, CD40 crosslinking by a monoclonal anti-CD40 antibody induces proliferation and tyrosine phosphorylation in B cells, suggesting that CD40 is a receptor that signals [25]. Indeed, CD40 signals through nuclear factor-kB to induce IL-12 production from APCs [26], and IL-12 selectively enhances CD40Lmediated IFN-g production [27]. In addition, soluble CD40L was shown to induce IL-10 production [28], and IL-10 overexpression in APCs resulted in exaggerated susceptibility to Leishmania infection [29]. These observations led to the concept that the CD40–CD40L interaction activates APCs via CD40 signals, thereby modulating the course of many infectious diseases. Whereas CD40 deficiency aggravates Mycobacterium avium infection associated with less IL-12 and IFN-g CD40–CD40LHi
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Figure 3. Proposed reciprocal regulation of T-cell functions and macrophage activation as a function of the extent of CD40–CD40L crosslinking. High levels of CD40–CD40L interaction activate macrophages and induce the production of IL-12, which skews Th0 (the precursor of Th subsets) to Th1. By contrast, low levels of interaction between CD40 and CD40L induce the production of IL-10, TGF-b and IL-2low from T cells, resulting in the deactivation of macrophages and the generation of Th2 and Treg cells. www.sciencedirect.com
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interaction between CD40 and CD40L could induce both Th1 and Th2 immune responses. As in all other infections, Th1-type and Th2-type responses were also implicated in HIV infection [43]. The induction of the Th1 differentiation-inducing cytokine IL-12 is shown to be defective owing to downregulation of CD40L on CD4CT cells in HIV patients [44]. Because the CD4CT-cell-expressed CD40L interacts with CD40 on CD8CT cells, enhancing the generation of memory CD8CT cells [45], CD40 signaling in CD8CT cells remains to be correlated with their effector functions, such as controlling viral replication and HIV-suppressive b-chemokine induction [46]. CD40 is also required for the production of anti-HIV antibodies [47]. Altogether, these studies indicate that CD40 does activate the immune system to protect the host. CD40-induced immunosuppression Because the host and the pathogens (parasites in particular) coevolved, pathogens might devise strategies to bypass or subvert the CD40-induced host-protective immune responses at two levels: first, downregulation of CD40 functions and, second, induction of T cells with suppressor functions. Because CD40 has been shown to induce IL-10 in macrophages [48] and TGF-b production in B cells [49], the TGF-b production from Leishmania-infected macrophages [50] might be induced by CD40. Because these cytokines might execute immunosuppression, favoring the persistence of pathogens such as Leishmania [48,50], an indiscriminate suppression of CD40 functions would prove detrimental to these pathogens. Therefore, it is logical to assume that pathogens might differentially regulate the CD40-induced production of both antiparasitic and pro-parasitic cytokines. Indeed, in Leishmania-infected macrophages, CD40-induced IL-10 secretion is increased, whereas IL-12 production is reduced [48], setting up the paradox of CD40 functions that favor both the parasite and the host. By contrast, the regulatory T cells (Tregs) with suppressor functions were proposed to maintain immune homeostasis. Both CD40-deficient mice and antiCD40L antibody-treated mice have fewer Treg cells in peripheral blood, thymus and spleen, suggesting that CD40 has a key role in Treg generation [51]. CD40deficient mice failed to maintain injected wild-type Treg cells, suggesting a role for CD40 in creating the milieu required for Treg maintenance. Because CD40 can induce the countereffective cytokines IL-12 and TNF-a versus IL-10 and TGF-b, as a function of strength of CD40 signaling, it is possible that Treg cells maintain low CD40L expression levels on their surface, or that the APCs responsible for Treg generation express low level of CD40. Thus, the nature of the CD40 signal might control the generation and maintenance of Treg cells (Figure 3). CD40 at the molecular level: reciprocal regulation of mitogen-activated protein kinases The preceding discussion indicates that CD40 stimulation can lead to either stimulatory or suppressive immune reactions. However, the molecular mechanisms remain unknown. We have shown that CD40 crosslinking at high doses results in p38 mitogen-activated protein (MAP) www.sciencedirect.com
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kinase-dependent IL-12 induction, whereas it induces extracellular-signal-regulated kinase (ERK)-1 and ERK2-mediated IL-10 production at low doses [48]. p38MAP kinase and ERK are known to be reciprocally regulated because inhibition of one activates the other and vice versa. During Leishmania infection, the levels of CD40induced ERK-1 and ERK-2 phosphorylation and IL-10 production increase, whereas the reverse profile was observed with p38MAPK activation and IL-12 production. These observations not only explain the paradox of CD40 functions eliciting both inflammatory and antiinflammatory immune responses, but also exemplify how pathogens manipulate the CD40 signal to render a hostile cell as their ‘safe home’ (Figure 4). Future perspectives The observed conundrum of CD40 functions not only reveals a new facet of immune homeostasis, but also helps to formulate immune intervention strategies. On the one hand, this phenomenon shows how CD40 can maintain the host-protective immunity in a reciprocal setup. During infection, CD40-activated T-cell responses eliminate pathogens, whereas in healthy individuals, they maintain immune silence by regulating Treg populations. Therefore, it is possible to devise a strategy for silencing immune reactivity against the allograft or against autoantigens. On the other hand, it remains to be explored how the
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Figure 4. Proposed molecular mechanism of the reciprocal regulation of CD40induced counteractive effector functions. At high doses of crosslinking, CD40 activates p38MAP kinase to induce IL-12 and iNOS2. Whereas IL-12 induces Th1 cells, iNOS2 catalyzes the generation of nitric oxide, the free radical that kills Leishmania amastigotes. At lower doses of crosslinking, CD40 activates ERK-1 and ERK-2, thereby inducing IL-10, which works in an autocrine manner to inhibit the CD40-induced activation of p38MAP kinase and the induction of IL-12 and iNOS2, resulting in disease promotion. IL-10 also has a role in Treg generation and maintenance. Thus, CD40 can provide both host protection and disease promotion by triggering reciprocal signaling pathways as a function of the extent of crosslinking. The other possible factors in this reciprocity of CD40 signaling could involve the differential recruitment of TNF-a-receptor-associated factors (TRAFs) 1–6 and phosphatases.
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initial CD40 ligation results in differential activation of p38MAP kinase or ERK-1 and ERK-2. The bifurcation of CD40 signaling might occur upstream of these MAP kinases (Figure 4) or right on the membrane, owing to differential clustering of CD40 with different signaling molecules. The importance of receptor clustering has been implicated not only in CD40 signaling [52], but also in TNF receptor signaling [53–56]. In addition, despite a great beneficial effect of anti-CD40 antibody administration in the mouse [48], recent reports on the role of Toll-like receptors in various immune responses suggest that, in vivo, a source of Toll-like receptor stimulation is necessary for an optimal effect of CD40 signal manipulation [57,58]. Nevertheless, more in vivo work is required to validate fully all of this interesting information derived from in vitro experimentation. Acknowledgements Our work is supported by the Department of Biotechnology, Government of India. R.K.M. and A.A. are supported by a fellowship from the Indian Council of Medical Research and the Council of Scientific and Industrial Research, respectively. We thank Debashis Mitra for critically reviewing the manuscript. Many references could not be cited owing to space constraints.
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ICOPA XI International Congress of Parasitology 6–11 August 2006, Scottish Exhibition and Conference Centre Glasgow, UK The scientific programme covers a diversity of research areas and is directed at a global audience. Although there are many defined themes, there is scope for presentations about any aspect of parasitology. The full programme also contains over 200 invited speakers, covering a broad range of expertise. This is the world’s largest parasitology congress, and Glasgow provides an excellent venue in which to hold it. We hope that you will attend and also encourage your colleagues to do so. We look forward to seeing you there. Register early at a reduced rate until 17 March 2006. (You are invited to contact the secretariat to discuss the possibility of late abstract submission.) For further information and online registration, go to www.icopaxi.org ICOPA XI Conference Secretariat c/o Meeting Makers Jordanhill Campus 76 Southbrae Drive Glasgow UK G13 1PP Tel: +44 (0) 141 434 1500 Fax: +44 (0)141 434 1500 Email: [email protected]
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